Frequency and characteristics of endometrial carcinoma and atypical hyperplasia detected on routine infertility investigations in young women: a report of six cases.

Infertility patients are known to be at increased risk of endometrial carcinoma (EC) and atypical hyperplasia (AH). However, the incidence and clinical features of EC and AH in these patients remain to be clarified. In this study, we examined the rate at which a routine infertility workup revealed EC/AH and investigated the clinicopathological features of EC/AH detected in this way. Among patients diagnosed with EC or AH at the Jichi Medical University Hospital between the 10-year period from 1997 to 2006, six patients were referred from Tochigi Central Clinic, a specialized infertility facility. We report the clinicopathological features of these patients and calculate the incidence of EC/AH in patients who underwent infertility investigations at Tochigi Central Clinic. All six patients were younger than 40 and had early stage disease (final diagnosis: EC stage IA: 3, EC stage IB: 1, AH: 2). A total of 19 826 patients underwent routine infertility investigations at Tochigi Central Clinic during the same period. The incidence of EC/AH detected from these investigations was 0.03% (6/19 826) and that of EC was 0.02% (4/19 826): 5-10 times higher than the overall incidence in Japanese women of the same age. Routine infertility investigations may provide an opportunity to examine the corpus uteri of young women in whom examination is otherwise limited, contributing to the early detection of EC/AH.

Omental metastases in clinical stage I endometrioid adenocarcinoma.

The clinical benefit of an omentectomy in endometrioid adenocarcinoma is unclear. The objective of this study was to clarify the significance of an omentectomy performed for clinical stage I endometrioid adenocarcinoma. A prospective study was performed on 134 patients with clinical stage I endometrioid adenocarcinoma who underwent omentectomy in addition to a staging laparotomy between 1998 and 2004: simple total hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node dissection, and peritoneal cytology. The frequency and prognosis of omental metastases and their relationships with extrauterine spread to other sites were investigated. Omental metastasis was noted in four patients (3.0%). As for extrauterine spread, the positivity rate of lymph node metastases was 13/128 (10.2%), peritoneal cytology was 13/133 (9.8%), and adnexal metastases was 10/134 (7.5%). Omental metastases correlated with peritoneal cytology and adnexal metastases (P < 0.05 for both); however, two of the omental metastases-positive patients were peritoneal cytology negative. All omental metastases-positive patients died shortly after surgery, showing that their prognosis was poor. The omental metastases rate for clinical stage I endometrioid adenocarcinoma was lower than the positive rates for extrauterine spread to other sites; thus, the routine application of omentectomy as a part of a staging laparotomy may not be efficacious. However, omental metastases are a significant poor prognostic factor, and intraoperative examination of the omentum by close inspection and palpation as well as pathologic examination, if possible, may be indicated.

Long-term follow-up study of patients with phenylketonuria detected by the newborn screening programme in Japan.

The objective of this report is to determine the need for and value of the long-term follow-up study of phenylketonuria (PKU) patients detected by newborn screening (NBS) in Japan. NBS was started in 1977 and the nationwide follow-up study of the identified patients was introduced into the NBS system. Outcome data from the continuous follow-up study showed in 1993 that IQ of PKU patients was inversely correlated with blood phenylalanine levels. Accordingly, in 1995, new treatment guidelines were issued that involved more stringent restriction of phenylalanine levels. Follow-up data confirmed that mean blood phenylalanine levels decreased after the introduction of the new guidelines, which included the recommendation to start dietary treatment within 20 days postpartum. Follow-up data also confirmed that dietary treatment did in fact commence earlier after the guidelines were issued. The need for lifelong dietary treatment is a difficult issue and the number of patients who stop dietary treatment was found to increase gradually with age. At present 60% of PKU patients born between 1977 and 1981 have stopped their dietary restriction of phenylalanine. The data gained from NBS and the long-term follow-up study were found to be valuable for the improvement of blood phenylalanine levels for patients with PKU, indicating the need for parties responsible for NBS and the follow-up study of the identified patients to work cooperatively. Further, the evaluations of the effectiveness of the two initiatives as well as the treatment guidelines issued should be based on outcome data, which depend on the continuation of the follow-up study of patients with PKU.

C-kit overexpression in neuroendocrine small cell carcinoma of the uterine cervix.

PURPOSE OF INVESTIGATION: Neuroendocrine small cell carcinoma of the uterine cervix (NESCC) grows aggressively, and is resistant to anticancer agents and radiation, having an extremely poor prognosis. The incidence of c-kit proto-oncogene overexpression is high in gastrointestinal stromal tumors (GISTs) and small cell lung cancer, and tyrosine kinase inhibitors have been used effectively to treat GISTs. Few studies have investigated whether c-kit is overexpressed in NESCC. To investigate whether NESCC can be a target for molecular targeted therapy with tyrosine kinase inhibitors, we examined the expression of c-kit in this tumor. METHODS: Twenty-one NESCCs were examined for c-kit expression by immunohistochemical staining using the labeled streptavidin-biotin complex (LSAB) method. The expression of c-kit was regarded as positive (overexpression) and negative when the membrane and cytoplasm of more or less than 25%, respectively, of tumor cells were stained. RESULTS: Nine NESCCs (43%) were c-kit-positive (overexpression). No difference in age or clinical stage was noted. No difference in prognosis was observed between the c-kit-positive and -negative patients. CONCLUSION: The incidence of c-kit overexpression was high in NESCC; therefore, the patients with this tumor may become a future target for molecular-targeted therapy with tyrosine kinase inhibitors.

Macrophage colony-stimulating factor as a tumor marker for epithelial ovarian cancer.

OBJECTIVE: To determine the serum level of macrophage colony-stimulating factor in ovarian cancer patients in order to evaluate its role as a marker for ovarian cancer. METHODS: Serum macrophage colony-stimulating factor levels were assayed in 69 patients with epithelial ovarian cancer, 55 with benign ovarian tumors, and 634 healthy individuals, including 398 women, using an enzyme-linked immunosorbent assay. RESULTS: The average serum macrophage colony-stimulating factor level was 754.4 +/- 153.9 U/mL in healthy females; 1056 U/mL (mean plus 1.96 standard deviations) was considered to be the upper limit of normal. Serum macrophage colony-stimulating factor levels were significantly elevated in patients with ovarian cancer (average 1460.5 +/- 1006.2 U/mL; P < .001) and exceeded 1056 U/mL in 42 of the 69 patients with ovarian cancer (61%). No differences in levels were observed among the histologic types. No definite relationship was found between serum levels of macrophage colony-stimulating factor and those of CA 125. We found that 96% of the patients with ovarian cancer had high serum levels of macrophage colony-stimulating factor and/or CA 125 values. There was no significant difference in the levels of macrophage colony-stimulating factor between patients with benign ovarian tumors and healthy controls. Only 7.3% of the group with benign tumors had levels exceeding 1056 U/mL. CONCLUSION: Macrophage colony-stimulating factor is a marker for ovarian cancer. Determination of serum levels can be useful in detecting ovarian cancer, particularly in combination with CA 125.

DNA replication errors are frequent in mucinous cystadenocarcinoma of the ovary.

To elucidate the genetic etiology of sporadic epithelial ovarian carcinoma, we examined replication errors (RER) in its two common types, serous cystadenocarcinoma (SAC) and mucinous cystadenocarcinoma (MAC). The subjects were 63 patients with sporadic epithelial ovarian carcinoma, consisting of 34 patients with SAC and 29 with MAC. The specimens were formalin-fixed and paraffin-embedded tissues from the ovary. The presence of RER was examined by polymerase chain reaction using 5 microsatellite markers. Of the 61 informative patients with ovarian carcinoma, RERs were observed at greater than or equal to 1 locus in 15 patients (25%). Four of the 32 SAC patients (13%) were RER-positive, and 11 of the 29 MAC patients (38%) were RER-positive, the incidence being significantly higher in the latter than in the former (P < 0.05). The incidence of RER was not related to the patients' age, stage, histologic grade, or prognosis. The MAC patients in stages I and II showed a relatively high incidence of RER (30%). These results suggest that RER are involved in the development and/or progression of MAC among sporadic epithelial ovarian carcinoma in its relatively early stage.

Mutation of K-RAS protooncogene and loss of heterozygosity on 6q27 in serous and mucinous ovarian carcinomas.

The genetic etiology of serous and mucinous ovarian carcinomas was investigated in 76 affected patients, focusing on the possible loss of heterozygosity (LOH) involving chromosome band 6q27 and K-RAS mutations at codon 12. The incidence of LOH in 6q27 (6q27 LOH) was 41% in 64 informative cases; 53% (20/38) and 23% (6/26) in cases of serous ovarian carcinoma and in those of mucinous ovarian carcinoma, respectively, indicating that the incidence of 6q27 LOH was significantly higher in cases of serous ovarian carcinoma (P < 0.05). The incidence of K-RAS mutations at codon 12 was 23% (15/64); 5% (2/38) and 50% (13/26) in cases of serous ovarian carcinoma and in those of mucinous ovarian carcinoma, respectively, indicating that the incidence of the K-RAS mutations was significantly higher in cases of mucinous ovarian carcinoma (P < 0.0001). Thus, K-RAS mutations at codon 12 and 6q27 LOH were suggested to be involved in the development and/or progression of mucinous ovarian carcinoma and serous ovarian carcinoma, respectively.

Are DNA mismatch repair deficiencies responsible for accumulation of genetic alterations in epithelial ovarian cancers?

To investigate the association of DNA mismatch repair deficiencies in the development and/or progression of epithelial ovarian cancers, the relationship between replication errors (RERs) and genetic alterations in three genes (p53, c-erbB2, K-ras) and loss of heterozygosity (LOH) on 6q27 was investigated in 70 patients with epithelial ovarian cancers. The presence of RERs was examined by PCR using five microsatellite markers. Mutations of p53 were analyzed by PCR-SSCP and sequencing. Amplification of c-erbB2 was analyzed by Southern blot hybridization. Point mutations of K-ras codon 12 were identified by PCR-PHFA, while 6q27LOH was examined by Southern blot hybridization. As a result, 18 of 70 patients with epithelial ovarian cancers (26%) were RER-positive and 52 patients (74%) were RER-negative. Tumors with two or three genetic alterations accounted for 28% and 33% of RER-positive tumors, respectively, and these were significantly more frequent than in the RER-negative tumors (17% and 6%, respectively)(P =.002). These results are consistent with mismatch repair deficiencies being involved in the development and/or progression of a proportion of epithelial ovarian cancers through accumulation of genetic alterations.

DNA replication error is frequent in ovarian granulosa cell tumors.

DNA replication errors (RER) have been detected in epithelial ovarian cancers, as well as in other human tumor types. These observations suggest that this genetic defect is present in ovarian granulosa cell tumors, and that a DNA mismatch repair deficiency may be involved in their development and/or progression. We therefore assayed tissue samples from 29 patients with granulosa cell tumors for RER, using polymerase chain reaction (PCR) and 5 microsatellite markers. The RER were observed at greater than or equal to 1 loci in 15 (58%) of 26 informative cases. The incidence of RER was unrelated to the patient's age or the histologic subtype or clinical stage of the tumors. The RER, however, were observed in 57% (8/14) of the informative patients with stage IA disease. These findings suggest that a DNA mismatch repair deficiency may contribute to the pathogenesis of ovarian granulosa cell tumors, and that this deficiency may be an early event in their development and/or progression.

DNA replication error in endometrial carcinoma and complex atypical endometrial hyperplasia.

We attempted to define the relation between DNA replication errors (RERs) in endometrial carcinomas and the precancerous lesion complex atypical endometrial hyperplasia (ATH) and clinicopathological characteristics. Tissue samples from 93 patients with endometrial carcinoma diagnosed as endometrioid adenocarcinoma and 26 patients with ATH (including 21 in whom endometrial carcinoma also was found) were prepared as formalin-fixed, paraffin-embedded sections. The samples were examined for the presence of RERs by the polymerase chain reaction with the use of five microsatellite markers. RERs were observed at > or = 1 loci in 32 endometrial carcinoma patients (34%); all 26 ATH patients were RER negative. RERs were observed in 25% of stage I and stage II cancer patients (16/64) and in 55% of stage III and stage IV cancer patients (16/29) (P = 0.009), as well as in 63% (10/16) of cancer patients with and in 27% (20/75) of patients without lymph-node metastases (P = 0.013). The incidence of RERs was not related to patient age, histological tumor grade, or prognosis. These results suggest that RER may be involved in the advanced rather than the early stages of endometrioid adenocarcinoma. There appears to be little association between RER and ATH.

New endoscopic treatment for chronic pancreatitis, using contrast media containing ulinastatin and prednisolone.

The preventive effects of contrast media containing ulinastatin (UST) and/or prednisolone (PDN) on potential complications associated with endoscopic retrograde cholangiopancreatography (ERCP) were studied in 111 patients. The incidence of abdominal pain and the elevation in the serum amylase level after ERCP were lower in the UST group than in the control group and abdominal pain and the elevated serum amylase level were almost completely suppressed in the PDN and UST/PDN groups. Based on these findings, a comparative study was conducted to evaluate the effectiveness of a combination of UST and PDN, given via the pancreatic duct, in alleviating pain symptoms in 57 patients with chronic pancreatitis and abdominal pain. The post-ERCP serum amylase level in some patients in the PDN and UST/PDN groups was lower than the pretreatment value. After ERCP, the abdominal pain that had been experienced before ERCP was relieved, and the value of the bentiromide-paraaminobenzoic acid (BT-PABA) test had improved. These results suggest that the use of contrast media containing PDN or UST/PDN in patients with chronic pancreatitis is extremely effective not only for preventing potential complications related to ERCP but also as a new diagnostic treatment method.

Apoptosis as a criterion for sensitivity of uterine cervical adenocarcinoma to cisplatin.

Two patients with uterine cervical adenocarcinoma received two courses of intra-arterial cisplatin administration. In the specimens of cervix 24 or 48 h after chemotherapy, marked apoptosis were observed. These bulky cervical tumors almost disappeared, and good PRs were confirmed by CT before operation. Apoptosis which is observed in the tissues of cervical adenocarcinoma 24 or 48 h after intra-arterial infusion of cisplatin, might be a new criterion of this chemotherapy effect.

Rapid death following papillary serous carcinoma of the endometrium without myometrial invasion.

A 72-year-old woman was diagnosed with a stage I endometrial carcinoma, and total hysterectomy, bilateral salpingo-oophorectomy, and systematic pelvic and paraaortic lymphadenectomy were performed. Postoperative pathological examination determined that the tumor was confined to the endometrium, with no myometrial invasion or lymph-vascular involvement; histological examination revealed a papillary serous carcinoma of the endometrium. Peritoneal washing cytology during surgery revealed an adenocarcinoma. Despite postoperative adjuvant chemotherapy, early recurrence resulted in death 13 months after surgery. In the absence of myometrial invasion and lymph-vascular involvement, the data suggest that peritoneal washing cytology may serve as a prognostic factor in papillary serous carcinoma of the endometrium.

Mutational analysis of transforming growth factor beta receptor type II and DNA mismatch repair genes in sporadic endometrial carcinomas with microsatellite instability.

To clarify how microsatellite instability (MI) is involved in carcinogenesis of sporadic endometrial carcinoma, we examined mutations of the transforming growth factor beta receptor type II (TGF beta RII) gene in 32 patients with MI-positive sporadic endometrial carcinoma. Moreover, mutations of 4 DNA mismatch repair (MMR) genes (hPMS1, hPMS2, hMLH1, hMSH2), which are considered to cause MI, were investigated as well. With respect to the TGF beta RII gene, mutations in the 10-bp polyadenine repeat sequence were observed in 7 of 29 informative cases (24%). Concerning MMR genes, a T to C point mutation at the -6 intronic splice acceptor site of exon 13 of hMSH2 was detected in 43% (6/14). However, there was no mutation in any exon of these 4 MMR genes. These results suggest that there is a carcinogenic mechanism via mutation of the TGF beta RII gene in some cases of MI-positive sporadic endometrial carcinoma. It seems unlikely that the unknown MMR genes are responsible for MI. The implication of the mutation at the intronic splice acceptor site in hMSH2 remains to be clarified.

Loss of heterozygosity on chromosome 6q27 and p53 mutations in epithelial ovarian cancer.

Loss of heterozygosity (LOH) in chromosome region 6q27 and p53 mutations were studied to attempt to clarify the genetic etiology of ovarian cancer, with particular reference to clear cell adenocarcinoma (CCC), which has a poor prognosis. 6q27 LOH in 70 epithelial ovarian cancer patients was examined using four restriction fragment length polymorphism markers located at 6q27; p53 mutations in tumor DNA were detected using polymerase chain reaction single-strand conformation polymorphism and sequencing. 6q27 LOH was confirmed in 26 of 48 informative cases (54.2%). No differences in the incidence of 6q27 LOH were seen by histologic type; 6q27 LOH was observed in 45% (5/11) of CCCs. p53 mutations were detected in 19 of the 48 tumors (39.6%), but in only one (9%) CCC. These results suggest that a putative tumor suppressor gene involved in the onset of epithelial ovarian cancer is located at 6q27. This gene is one of the keys to clarifying the genetic etiology of epithelial ovarian cancer and particularly CCC, given the low incidence of p53 mutations in this tumor type.

Appearance of primary endometrial and ovarian clear cell adenocarcinoma 17 months postpartum. A case report.

BACKGROUND: Rare cases of endometrial cancer have been reported within two years postpartum. However, clear cell adenocarcinoma of the endometrium does not appear to have been reported before as occurring in the early postpartum period. CASE: A 33-year-old-female experienced abnormal uterine bleeding 17 months after the delivery of her second child by cesarean section. Computed tomography indicated the presence of tumors in the uterus and cul-de-sac. Preoperative evaluation of endometrial cytology revealed adenocarcinoma cells. These cells demonstrated a centrally located nucleus and translucent, clear cytoplasm, with the so-called mirror ball pattern of cell clusters. The cytologic diagnosis was clear cell adenocarcinoma. Postoperative histologic evaluation verified the presence of a solid type of clear cell adenocarcinoma. The patient was considered to have simultaneous primary clear cell adenocarcinoma of the endometrium and ovary. CONCLUSION: Preoperative endometrial cytology correctly suggested the histologic type of cancer.

Primary malignant lymphoma of the uterine corpus diagnosed by endometrial cytology. A case report.

BACKGROUND: A relatively small number of cases of primary malignant lymphoma of the uterine corpus have been reported, and it is rare for cases to be preoperatively diagnosed by cytology. CASE: A 59-year-old female experienced abnormal uterine bleeding of two months' duration. Preoperative evaluation of endometrial cytology revealed malignant cells. These cells demonstrated a rather round or oval configuration, with a markedly increased nuclear/cytoplasmic ratio, and were isolated and scattered in an inflammatory background. The nuclei were round or oval, and macronucleoli were marked. The cytologic diagnosis was malignant lymphoma. Postoperative histologic evaluation verified the presence of a primary malignant lymphoma in the uterine corpus, with a B-cell phenotype. CONCLUSION: Preoperative endometrial cytology correctly demonstrated malignant lymphoma of the uterine corpus.

The value of pre-operative diagnostic procedures for cervical involvement in uterine corpus carcinoma.

OBJECTIVE: To assess the value of procedures for pre-operative diagnosis of cervical involvement of uterine corpus carcinoma. MATERIALS AND METHODS: Four diagnostic procedures, including cervical cytology, endocervical curettage (ECC), magnetic resonance imaging (MRI), and hysteroscopy, were performed for diagnosis of cervical involvement in 60 patients with uterine corpus carcinoma. The preoperative diagnosis based on results obtained using by each procedure was retrospectively compared with the diagnosis based on histological examination of surgical specimens. Data were analyzed according to the standard definition of sensitivity, specificity, positive predictive value and negative predictive value. RESULTS: Cervical involvement was confirmed in 18 patients (30%). ECC showed high sensitivity (90.9%) and specificity (88.9%). Cervical cytology showed high specificity (88.6%). MRI showed very high specificity (99.2%) and high sensitivity (88.5%) in cases with cervical stromal invasion. CONCLUSION: Cervical cytology and MRI are useful for excluding cervical involvement. ECC is useful for positive diagnosis. MRI may be useful for cases with stromal invasion. The use of a combination of several procedures is essential for obtaining an accurate diagnosis of cervical involvement in cases of uterine corpus carcinoma.

[Clinical evaluation of serum CA-50 and CA 19-9 in gynecological tumors].

We conducted a study to evaluate cancer associated antigen CA-50 and CA 19-9 as tumor markers of gynecological malignancies. The positive rates of CA-50 and CA 19-9 for ovarian cancer were 35.5% and 48.8%, respectively, and thus were not very high. In terms of histological typing, relatively high positive rates were noted in mucinous type-42.9% for CA-50 and 71.4% for CA 19-9. Both antigens showed high false positive rates for benign ovarian tumors, especially for dermoid cyst, but produced few false positive cases of endometrial cyst. For cervical cancer and endometrial cancer, these antigens were positive at low rate. In conclusion, the present evaluation indicated that both CA-50 and CA 19-9 do not necessarily suffice as screening markers for gynecological malignancies; that they could potentially be of help for diagnosis of ovarian cancer of mucinous type; and that their false positive rates for endometrial cyst were very low.

[A study of an autosomal recessive polycystic kidney disease with facial and skeletal abnormalities in rat].

Clinico-pathological studies were made on rats with polycystic kidney disease (PCK), a congenital renal disorder transmitted as an autosomal recessive trait and characterised by facial and skeletal anomalies, with the results summarised as follows: 1) Affected animals had a poor weight gain and slightly increased urinary excretion of low molecular weight protein from 2 months after birth, and developed polyuria and hypocalciuria 5 months postnatally. They had elevation of serum urea nitrogen, increased urinary excretion of urea nitrogen and hypoproteinemia 8 months postnatally though without showing elevated serum creatinine and died around 10 months of life. 2) Kidneys of chin rats appear granular in surface, enlarge little by little while preserving the entire kidney morphology; a small cyst is formed in the renal medulla 2 months postnatally, then enlarges gradually to encroach upon the cortex and grows to involve all cortical layers by 8 months of life. This cyst was revealed by lectin staining to be derived from the collecting ducts and was assumed to correspond, both morphologically and clinically, to the infantile or juvenile form of PCK in humans. Pathogenetic factors of the characteristic facies and skeletal abnormalities were also investigated.